Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment.

Journal article

Synaptic-vesicle exocytosis is mediated by the vesicular Ca(2+) sensor synaptotagmin-1. Synaptotagmin-1 interacts with the SNARE protein syntaxin-1A and acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). However, it is unclear how these interactions contribute to triggering membrane fusion. Using PC12 cells from Rattus norvegicus and artificial supported bilayers, we show that synaptotagmin-1 interacts with the polybasic linker region of syntaxin-1A independent of Ca(2+) through PIP2. This interaction allows both Ca(2+)-binding sites of synaptotagmin-1 to bind to phosphatidylserine in the vesicle membrane upon Ca(2+) triggering. We determined the crystal structure of the C2B domain of synaptotagmin-1 bound to phosphoserine, allowing development of a high-resolution model of synaptotagmin bridging two different membranes. Our results suggest that PIP2 clusters organized by syntaxin-1 act as molecular beacons for vesicle docking, with the subsequent Ca(2+) influx bringing the vesicle membrane close enough for membrane fusion.

Authors: Honigmann, A; van den Bogaart, G; Iraheta, E; Risselada, H; Milovanovic, D

• Publication status: Published
• Journal: Nature structural and molecular biology
• Volume: 20
• Issue: 6
• Pages: 679-686
• Publication date: 2013-06-01
• DOI: 10.1038/nsmb.2570
• EISSN: 1545-9985
• ISSN: 1545-9993
• Language: English
• Keywords: Exocytosis; Synaptic Vesicles; Syntaxin 1; Phosphatidylinositol 4,5-Diphosphate; Protein Conformation; Synaptotagmin I; Protein Binding; Animals; Models, Molecular; Models, Biological; Crystallography, X-Ray; Rats; PC12 Cells